Highlights from Stuyvesant’s Celebrate Research Night

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By Matt Melucci

The Regeneron Science Talent Search is the most prestigious science research competition for high school seniors across the United States. Each year, Stuyvesant’s brightest student scientists join laboratories at esteemed institutions like New York University and Memorial Sloan Kettering Cancer Center to perform experiments, write scientific papers, and develop winning submissions to the competition.

Radiation repairs specific types of cancers

Senior Janen Khan has spent her past three summers doing research: first studying at the Harlem DNA lab and later interning at Columbia University. Khan reflects that her earlier stages at Columbia rooted in her a “deep investment to discover the promising field of work that researching the genome provides in the study of life.” This led her to Weill Cornell Medical Center, where she spent more than eight hours a day at the Oncology and Radiation Lab over the summer.

At Weill Cornell, Khan researched the impact of different variables on cells lacking the Phosphatase and Tensin Homolog (PTEN) gene. The PTEN gene is a tumor suppressor that plays a role in fighting many types of cancers and regulates the cell cycle. Cells that have unregulated tumor suppressors—such as those lacking the PTEN gene—are likely to develop cancer. Khan explained that “the loss of PTEN primarily results in cells exhibiting cell cycle deregulation and fate reprogramming.”

Her research focused on radiation treatment’s impact on the growth of engineered PTEN-deficient cancer cells. She constructed these PTEN-deficient cells by modifying histones, proteins that interact with DNA, thus preventing the production of PTEN. “If I introduce a mutation into a plasmid, the plasmid will produce the effects of the mutations. It’s like mimicking what cancer patients have,” Khan said. The resulting cells had mutated PTEN genes and therefore lacked the PTEN protein.

These cancer-prone PTEN-deficient cells were subjected to radiation therapy, a method of killing rapidly dividing cells. Analyzing the results of the radiation was not an easy feat. According to Khan, she “...had to analyze 5,000 photos and foci of each cell, [which had] at least a minimum of 100 cells per photo. I took five photos per each [result]. It took me several hours.”

When she saw the results, she was stunned. “What we want to see is fewer foci, but I saw more. [This] meant that the cancer cells were actually repairing themselves, which is a bad thing,” Khan explained. “They were growing. [The radiation treatments] were causing them to abruptly divide.” PTEN mutations are increasingly being linked with cancer but are still poorly understood. By performing more research on the effects of these mutations and how to combat them, we can transform the way cancer therapy is delivered. The most prevalent cancers today, such as colorectal and prostate cancer, are affiliated with high levels of PTEN mutations. This makes cutting-edge epigenetic therapies targeting PTEN transcription especially promising.

Cancer continues to be a major cause of death worldwide. Understanding different mechanisms of the disease is vital for developing and regulating new treatments. Khan is an advocate of research, especially research related to medical applications. “No matter how much we progress in life as a society with technology, if we can’t ensure the well-being of our species and [that of] others, I feel that it depreciates the value of all the advancements,” Khan said. “Examining the basics of life will allow us to refine our techniques for finding cures to ‘incurable’ diseases and help us take leaps in progress.” Using inovation, pharmaceutical companies, researchers, and everyday people, like Janen Khan, can work to reduce the incidence of cancer.

The Effects of Cellular Growth Factor Deletions on Lung Cancer

Senior Eren Ucar is what you could call a “biology enthusiast,” to say the least. Ever since the age of 15, understanding the world around him and how it works has been his strongest passion. Throughout his middle and high school careers, he was always researching and pursuing problems that afflict humans every day. Over time, one particular topic captured his interest and stood out among the rest: lung cancer. In addition to Eren’s strong interest in lung cancer as a subject in biology, Eren was also drawn to the topic on a more personal note. Eren wrote in an e-mail interview, saying that “Since some of my own family members have been victims of lung cancer, I felt it would be a good use of my time to help in the effort to treat it.”

It wasn’t until the summer of 2019 that Eren tackled this disease during his research project at Weill Cornell Medicine, where he explored the most common subtype of lung cancer, lung adenocarcinoma (LUAD).

Lung cancer develops when a DNA mutation occurs within cells of alveolar tissue, leading to a rapid proliferation of cancerous cells throughout the respiratory tract. What baffles scientists about this disease is not only how difficult it is to cure, but also how the cancer cells themselves are able to evade cell checkpoints throughout the human body and continue dividing uncontrollably. Lung cancer is the most lethal cancer in the United States, taking more than 150,000 lives each year.

LUAD is driven by mutated growth factor receptors within cancer cells. These receptors—epidermal growth factor receptors (EGFRs)—are responsible for the extreme mutations and cell division that occur in lung cancer cells. In many instances, the cancer is able to overwhelm the body by hijacking the body’s cellular machinery in order to inactivate the normal tumor suppressors that prevent the cells from growing.

One of the most prominent tumor suppressor genes is retinoblastoma protein (RB1). RB1 prevents excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide and controls the the expression of transcription factors (NKX2-1 protein). Though LUAD patients are clinically treated with target therapies, these treatments often lead to the deactivation of these suppressor genes, specifically RB1.

Eren’s goal was to isolate specifically which segment of the RB1 gene is most responsible for preventing cancerous cell growth when working properly—and allowing this growth when malfunctioning. To address this, he chose to manipulate the known functional subgroups of RB1, domains A, B, and C, to determine which parts are required for NKX2-1 expression. In order to accomplish this, Eren generated a synthetic version of RB1 by assembling DNA fragments. He altered the expression of either domain A, B, or C in these synthetic fragments.

First, Eren genetically modified the RB1 gene so that it lacked one of the functional domains in each of his trials. By using quantitative PCR, a molecular research tool in which certain DNA or RNA fragments are highlighted within a sample, Eren observed the expression of the transcription factors over the course of seven days. His results demonstrated that the deletion of domains A and C did not impair the ability of RB1 to express the transcription factors of NKX1-2, whereas the deletion of domain B severely diminished the expression of the protein. Thus, domain B was most responsible for the gene’s vulnerability to LUADs.

This data reveals how crucial domain B is in expressing NKX2-1. Without the appropriate production and expression of NKX2-1, these malignant cancer cells have the ability to grow and divide until they metastasize to other parts of the body.

More importantly, this discovery offers an explanation as to why LUAD patients often develop a resistance to target therapies, and it might also offer a solution for future treatments. Now that scientists know the importance of domain B in preventing cancerous growth in lung tissue, they can begin devising a strategy as to how to protect the gene from being hijacked.

Even though developing a cure to cancer is a long and tedious process leading into the far future, Eren believes that every step in the right direction counts. “My research, or research in general, is not about always making the groundbreaking discovery. It is about discovering more about the human body and its intricacies,” Eren said. “It’s about pushing the needle ever so slightly, which in turn can lead to the discovery of major cures.”

Reaching Out to Older Adults with Mental Health Disorders in New York City

The term “science experiment” usually evokes an image of safety goggles, test tubes, and volatile chemicals in a lab. But to senior Justin Lam, a participant in the Regeneron Science Talent Search, it conjures up memories of number crunching and lengthy statistical analyses at the New York City Department for the Aging (DFTA) this past summer.

Lam’s social sciences project, “Reaching Out to Older Adults with Mental Health Disorders in New York City,” aimed to determine which groups of adults (generally older than 60 years) underutilize clinical services, including counseling, screening, and treatment planning. Then, armed with a better understanding of where patient outreach falls short, it would explore alternative methods of engaging those adults—more specifically, victims of mental health disorders.

Lam’s project took flight after making a special connection with the Director of Research at the NYC DFTA, Dr. Jackie Berman, and his mentor, Dr. Madison Gates. Working just a few blocks west of Stuyvesant, she had generously agreed to talk to Jason Econome’s Research Club one Friday afternoon about their team’s work.

Then, over the course of a few months, Lam applied inferential statistics––including chi-squared tests, kruskal-wallis tests, and logistic regression––to analyze data gathered from the DFTA’s 2016 Geriatric Mental Health Initiative. Concerning disparities immediately became apparent: Caucasians were four times more likely than Asians to use clinical services. White Hispanics spent about 246 days in clinical services, while African Americans only spent about 177. Around two-thirds of higher income groups used clinical services, while less than half of their lower income counterparts used these same services.

Seeing that minority groups or groups with low socioeconomic status are underutilizing clinical services, Lam hopes that his research will inspire new ways to spread mental health awareness. He is firm in his belief that financial and cultural barriers have no place in medicine, and that through new methods of outreach like non-clinical intervention services, the gap can be bridged.

On the Lac Operon in E. Coli

E. coli is one of science’s most extensively studied bacterial species, primarily because of its exceptional evolutionary capabilities. This has resulted in the creation of scores of different strains of E. coli. Senior Lily Jin found a way to keep track of them using a computer program that compares the bacteria’s genomes based on the lactose operon, a sequence of three genes that creates the enzymes necessary to derive energy from lactose. Lactose operons are further subdivided into sections of genes, each called LacO, LacP, LacI, LacZ, or LacY. By comparing lactose operon gene sequences between strains, Jin cleverly used this information to construct a detailed evolutionary tree of E. coli.

Her research is especially relevant because E. coli is evolving faster than modern medicine, and this research will allow scientists to more effectively understand and even predict its evolutionary patterns. She began by testing a pilot program that would analyze a small number of strains. This program was created by synthesizing the existing programs MUSCLE and BLAST, which are commonly used in genetic research, and then compare the DNA structure of the strains manually. MUSCLE, boasting a sequence alignment tool that can pinpoint and highlight specific DNA differences, proved useful. Jin then used the program BLAST to compare LacI, LacY, LacA, and LacZ genes between strains. Once she combined data for both, she was able to construct a comprehensive evolutionary history of E. coli.

The computerized results demonstrate that though the lactose operon remains relatively constant between strains, the differences, when they occur, are both noticeable and extensive. There appears to be more differences between the LacY and LacZ genes, which may give clues to their evolutionary role. Additionally, the order of these genes differs between strains; while the most common order follows as LacA, LacY, and LacZ, this seems to vary between strains. In this way, the order of such genes could prove to have some evolutionary significance.

E. coli infections prove to be lethal even in the modern day; that’s why research like Jin’s can have far-reaching impacts. Using her data on E. coli evolution, we may one day be able to find an effective cure for such infections. Jin plans to showcase her inventive work at the New York City Science and Engineering Fair in March, and may have yet more information on her research at the event.